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Method for synthesis of N-homocysteine thiolactonyl retinamide

Inactive Publication Date: 2000-04-25
BAYLOR UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

D. Carbodiimide Methods: When using carbodiimide, an activated intermediate, which is produced by reaction of a protected amino acid and the carbodiimide, undergoes aminolysis. The reaction of an N-protected amino acid and carbodiimide without an amine component gives another activated species, which also reacts with amine components. Water-soluble carbodiimides such as 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide have been developed, in such systems, both the reagent and the resulting urea derivative are soluble and easily removable by washing.
H. Phosphonium and Uronium Salt Type Coupling Reagents: benzotriazole-1-yloyxtris(dimethylamino)phosphonium hexafluorophosphate (bop) is an excellent coupling reagent offering high reactivity and easy handling. The reaction between bop and N-protected amino acid proceeds via an acyloxyphosphonium as an intermediate to produce the corresponding bonzotriazole ester and easily removable by-products such as hexamethylphosphoric triamide (hmpa) and salts. However, hmpa, the starting material the synthesis and a by-product in the reaction of bop, have been reported to have respiratory toxicity. It is therefore contemplated that bop can be replaced by benzotriazole-1-yloxytrspyrrolidinophosphonium hexafluorophosphate (pybop), which as similar reactivity to bop but forms no carcinogenic by-products.

Problems solved by technology

This produces large quantities of the desired product with few by-products.

Method used

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  • Method for synthesis of N-homocysteine thiolactonyl retinamide
  • Method for synthesis of N-homocysteine thiolactonyl retinamide
  • Method for synthesis of N-homocysteine thiolactonyl retinamide

Examples

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example 1

Synthesis of N-Homocysteine Thiolactonyl Retinamide

The compound produced by methods described in this invention, N-homocysteine thiolactonyl retinamide, is also abbreviated as thioretinamide. This compound is an N-substituted derivative of homocysteine thiolactone which is conjugated to retinoic acid or retinamide. Thioretinamide has antineoplastic, chemopreventive, and antiatherogenic properties. Synthesis of this compound by organic methods allows the investigation of the mechanisms of action of these properties. The steps involved in the synthesis of thioretinamide are as follows:

Synthesis of N-homocysteine thiolactonyl retinamide (thioretinamide) can also be carried out by alternative methods as disclosed herein. Under conditions of reduced light and an atmosphere of argon, all-trans-retinoic acid, 0.666 M (0.200 grams) (Sigma Chemical Co., Missouri), was dissolved in 20 ml of argon protected anhydrous tetrahydrofuran (THF). After stirring ten minutes, the transparent yellow sol...

example 2

Modifications for the Synthesis of Thioretinamide

All of the compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments in Example 1, it will be apparent to those of skill in the art that variations may be applied to the compositions and / or methods disclosed and in the steps or in the sequence of steps of the method described in Example 1 without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention are presented in this Example. For example, the factors can be changed in the procedure described in Example 1, without deviating from the scope of the invention.

Coupling Reagents

Different coupling agents, other than those described in...

example 3

Analysis of N-Homocysteine Thiolactonyl Retinamide

Verification of thioretinamide synthesis was performed by using proton and carbon N.M.R. and mass spectroscopy. The proton N.M.R. of thioretinamide (FIG. 2) shows both homocysteine thiolactone (FIG. 3) and retinoic acid (FIG. 4) as constituents of thioretinamide. The proton N.M.R. of thioretinamide (FIG. 2) at 1.0-2.4 ppm consists of singlet peaks integrating for the three methyl group hydrogens of the retinoic acid component of thioretinamide. Peaks at 2.9-4.6 ppm correspond to the protons of the homocysteine thiolactone ring of thioretinamide. The peaks at 5.7-7.0 ppm represent the unsaturated protons, vinyl protons, of the retinoic acid component of thioretinamide. The conjugation of homocysteine thiolactone and retinoic acid at the homocysteine thiolaconyl amide is indicated by downfield shifting of proton signals of the amide hydrogen thioretinamide N.M.R. The synthesis of thioretinamide reported by McCully and Vezeridis (1987a)...

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Abstract

The present invention describes a method of organic synthesis for N-homocysteine thiolactonyl retinamide, a compound that has anticancer and antiatherogenic properties.

Description

1. Field of the InventionThe present invention relates generally to the fields of organic synthesis of bioactive compounds. More particularly, it concerns the chemical method of synthesis for N-homocysteine thiolactonyl retinamide, a compound that has anticancer and antiatherogenic properties.2. Description of Related ArtChemotherapeutic agents such as cyclophosphamide which are commonly used as antineoplastic agents have the disadvantage of cumulative toxicity after prolonged administration in cancer chemotherapy. The subject compound of this invention, N-homocysteine thiolactonyl retinamide, overcomes the disadvantage of toxicity of chemotherapeutic compounds and retinoids, because it is composed of retinoic acid and homocysteine thiolactone bound together in a non-toxic form. Because large doses of N-homocysteine thiolactonyl retinamide can be given without toxicity, the compound is useful for chemoprevention and chemotherapy of malignant neoplasms in animals and for use as an an...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D333/00C07D333/32
CPCC07D333/32
Inventor KAZIMIR, MICHALWILSON, II, F. RAY
Owner BAYLOR UNIVERSITY
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